What if we never find a coron­avirus vac­cine?

Sci­en­tists on why politi­cians have be­come more cau­tious about the prospects of im­mu­ni­sa­tion – and why they are right to be

The Guardian - - Front Page - By Ian Sam­ple Sci­ence editor

The idea is to pro­tect against in­fec­tion, pre­vent its spread and do so safely. But decades of ex­pe­ri­ence with other diseases show this is far from straight­for­ward

‘If the nat­u­ral in­fec­tion doesn’t give you that much im­mu­nity ex­cept when it’s se­vere, what will a vac­cine do?’

It would be hard to over­state the im­por­tance of de­vel­op­ing a vac­cine to Sars-Cov-2 – it’s seen as the fast track to a re­turn to nor­mal life. That’s why the health sec­re­tary, Matt Han­cock, de­clared the UK was “throw­ing ev­ery­thing at it”.

But while tri­als have been launched and man­u­fac­tur­ing deals al­ready signed – Ox­ford Univer­sity is now re­cruit­ing 10,000 vol­un­teers for the next phase of its re­search – min­is­ters and their ad­vis­ers have be­come no­tice­ably more cau­tious in re­cent days.

Why might a vac­cine fail?

Ear­lier this week, Eng­land’s deputy chief med­i­cal of­fi­cer, Jonathan VanTam, said the words that no­body wanted to hear: “We can’t be sure we will get a vac­cine.”

But he was right to be cir­cum­spect. Vac­cines are sim­ple in prin­ci­ple but com­plex in prac­tice. The ideal vac­cine pro­tects against in­fec­tion, pre­vents its spread, and does so safely. But none of this is eas­ily achieved, as time­lines show.

More than 30 years after sci­en­tists iso­lated HIV, the virus that causes Aids, we have no vac­cine. The dengue fever virus was iden­ti­fied in 1943, but the first vac­cine was ap­proved only last year, and even then there were con­cerns it made the in­fec­tion worse in some peo­ple. The fastest vac­cine ever de­vel­oped was for mumps. The process took four years.

Sci­en­tists have worked on coron­avirus vac­cines be­fore, so they are not start­ing from scratch. Two coro­n­aviruses have caused lethal out­breaks be­fore, namely Sars and Mers, and vac­cine re­search went ahead for both. But none have been li­censed, partly be­cause Sars fiz­zled out and Mers is re­gional to the Mid­dle East. The lessons learned will help sci­en­tists cre­ate a vac­cine for Sars-Cov-2, but there is still an aw­ful lot to learn about the virus.

A chief con­cern is that coro­n­aviruses don’t tend to trig­ger long-last­ing im­mu­nity. About a quar­ter of com­mon colds are caused by hu­man coro­n­aviruses, but the im­mune re­sponse fades so rapidly that peo­ple can be­come re­in­fected the next year.

Re­searchers at Ox­ford Univer­sity re­cently an­a­lysed blood from re­cov­ered Covid-19 pa­tients and found that lev­els of IgG an­ti­bod­ies – those re­spon­si­ble for longer-last­ing im­mu­nity – rose steeply in the first month of in­fec­tion but then be­gan to fall again.

Last week, sci­en­tists at Rock­e­feller Univer­sity in New York found most peo­ple who re­cov­ered from Covid-19 with­out go­ing into hos­pi­tal did not make many killer an­ti­bod­ies against the virus. “That’s what is par­tic­u­larly chal­leng­ing,” says Stan­ley Perl­man, a vet­eran coron­avirus re­searcher at the Univer­sity of Iowa. “If the nat­u­ral in­fec­tion doesn’t give you that much im­mu­nity ex­cept when it’s a se­vere in­fec­tion, what will a vac­cine do? It could be bet­ter, but we don’t know.”

If a vac­cine only pro­tects for a year, the virus will be with us for some time. The ge­netic sta­bil­ity of the virus mat­ters too. Some viruses, such as in­fluenza, mu­tate so rapidly that vac­cine de­vel­op­ers have to re­lease new for­mu­la­tions each year. The rapid evo­lu­tion of HIV is a ma­jor rea­son why we have no vac­cine for the dis­ease.

So far, the Sars-Cov-2 coron­avirus

‘You don’t know the spe­cific dif­fi­cul­ties ev­ery vac­cine will give. And we haven’t got ex­pe­ri­ence in han­dling this virus’

seems fairly sta­ble but it is ac­quir­ing mu­ta­tions, as all viruses do. Some ge­netic changes have been spot­ted in the virus’s pro­tein “spikes”, which are the ba­sis of most vac­cines. If the spike pro­tein mu­tates too much, the an­ti­bod­ies pro­duced by a vac­cine will in ef­fect be out of date and may not bind the virus ef­fec­tively enough to pre­vent in­fec­tion. Martin Hib­berd, pro­fes­sor of emerg­ing in­fec­tious diseases at the Lon­don School of Hy­giene and Trop­i­cal Medicine, who helped iden­tify some of the virus’s mu­ta­tions, called them “an early warn­ing.”

An­other chal­lenge: mak­ing any vac­cine safe …

In the rush to de­velop a vac­cine – there are now more than 100 in de­vel­op­ment – safety must re­main a pri­or­ity. Un­like ex­per­i­men­tal drugs for the se­verely ill, the vac­cine could be given to po­ten­tially bil­lions of gen­er­ally healthy peo­ple.

This means sci­en­tists will have to check ex­tremely care­fully for signs of dan­ger­ous side-effects. Dur­ing the search for a Sars vac­cine in 2004, sci­en­tists found that one can­di­date caused hep­ati­tis in fer­rets.

An­other se­ri­ous con­cern is “an­ti­body-in­duced en­hance­ment”, where the an­ti­bod­ies pro­duced by a vac­cine ac­tu­ally make fu­ture in­fec­tions worse. The ef­fect caused se­ri­ous lung dam­age in an­i­mals given ex­per­i­men­tal vac­cines for both Sars and Mers.

John McCauley, di­rec­tor of the world­wide in­fluenza cen­tre at the Fran­cis Crick In­sti­tute in Lon­don, says it takes time to un­der­stand the par­tic­u­lar chal­lenges each vac­cine throws up. “You don’t know the dif­fi­cul­ties, the spe­cific dif­fi­cul­ties, that ev­ery vac­cine will give you,” he says. “And we haven’t got ex­pe­ri­ence in han­dling this virus or the com­po­nents of the virus.”

We should “end up with some­thing”, but what does that mean?

When the prime min­is­ter, Boris John­son, told a No 10 press brief­ing that a vac­cine was “by no means guar­an­teed”, his chief sci­en­tific ad­viser, Pa­trick Val­lance, agreed, but added: “I’d be sur­prised if we didn’t end up with some­thing.” Many sci­en­tists share that view.

In all like­li­hood, a coron­avirus vac­cine will not be 100% ef­fec­tive.

Those in de­vel­op­ment draw on at least eight ap­proaches, from weak­ened and in­ac­ti­vated viruses to tech­nolo­gies that smug­gle ge­netic code into the re­cip­i­ent’s cells, which then churn out spike pro­teins for the im­mune sys­tem to make an­ti­bod­ies against.

Ide­ally, a vac­cine will gen­er­ate per­sis­tent, high lev­els of an­ti­bod­ies to wipe out the virus, and also T cells to de­stroy in­fected cells. But each vac­cine is dif­fer­ent and to­day no one knows what kind of im­mune re­sponse is good enough. “We don’t even know if a vac­cine can pro­duce an im­mune re­sponse which would pro­tect against fu­ture in­fec­tion,” says David Hey­mann, who led the World Health Or­ga­ni­za­tion’s re­sponse to the Sars epi­demic.

Early re­sults from two fron­trun­ner vac­cines sug­gest they may have some use. A US biotech firm, Moderna, re­ported an­ti­body lev­els sim­i­lar to those found in re­cov­ered pa­tients in 25 peo­ple who re­ceived its vac­cine. A vac­cine from Ox­ford Univer­sity didn’t stop mon­keys con­tract­ing the virus but did ap­pear to pre­vent pneu­mo­nia, a ma­jor cause of death in coron­avirus pa­tients. If hu­mans re­acted the same way, vac­ci­nated peo­ple would still spread the virus but would be less likely to die from it.

How well a vac­cine works de­ter­mines how it is used. Armed with a highly ef­fec­tive vac­cine that pro­tects for sev­eral years, coun­tries could aim for herd im­mu­nity by pro­tect­ing at least two-thirds of the pop­u­la­tion.

Coron­avirus pa­tients pass the virus on to three oth­ers, on av­er­age, but if two or more are im­mune the out­break will fiz­zle out. That is the best-case sce­nario. More likely is we will end up with a vac­cine, or a num­ber of vac­cines, that are only par­tially ef­fec­tive.

Vac­cines that con­tain weak­ened strains of virus can be dan­ger­ous for older peo­ple, but may be given to younger peo­ple with more ro­bust im­mune sys­tems to re­duce the spread of in­fec­tion. Mean­while, older peo­ple may get vac­cines that sim­ple pre­vent in­fec­tions pro­gress­ing to life-threat­en­ing pneu­mo­nia. “If you don’t have the abil­ity to in­duce im­mu­nity, you’ve got to de­velop a strat­egy for re­duc­ing se­ri­ous out­comes of in­fec­tion,” says McCauley.

But par­tially ef­fec­tive vac­cines have their own prob­lems: a vac­cine that doesn’t stop the virus repli­cat­ing can en­cour­age re­sis­tant strains to evolve, mak­ing the vac­cine re­dun­dant.

So, is the virus here to stay?

The sim­ple an­swer is: yes. Hopes for elim­i­nat­ing the virus start with a vac­cine but do not end there.

“If and when we have a vac­cine what you get is not rain­bows and uni­corns,” says Larry Bril­liant, CEO of Pan­de­fense Ad­vi­sory, who led the WHO’s small­pox erad­i­ca­tion pro­gramme.

“If we are forced to choose a vac­cine that gives only one year of pro­tec­tion, then we are doomed to have Covid be­come en­demic, an in­fec­tion that is al­ways with us.”

The virus will still be tough to con­quer with a vac­cine that lasts for years. “It will be harder to get rid of Covid than small­pox,” says Bril­liant. With small­pox it was at least clear who was in­fected, whereas peo­ple with coron­avirus can spread it with­out know­ing. A thornier prob­lem is that as long as the in­fec­tion rages in one coun­try, all other na­tions are at risk.

As David Sal­is­bury, for­mer di­rec­tor of im­mu­ni­sa­tion at the Depart­ment of Health, told a Chatham House we­bi­nar re­cently: “Un­less we have a vac­cine avail­able in un­be­liev­able quan­ti­ties that could be ad­min­is­tered ex­traor­di­nar­ily quickly in all com­mu­ni­ties in the world we will have gaps in our de­fences that the virus can con­tinue to cir­cu­late in.” Or as Bril­liant puts it, the virus will “ping-pong back and forth in time and ge­og­ra­phy”.

‘If we are forced to choose a vac­cine that gives only a year of pro­tec­tion, we are doomed to have Covid be­come en­demic’

One pro­posal from Gavi, the vac­cine al­liance, is to boost the avail­abil­ity of vac­cines around the world through an “ad­vance mar­ket com­mit­ment”.

And Bril­liant be­lieves some kind of global agree­ment must be ham­mered out now. “We should be de­mand­ing, now, a global con­fer­ence on what we’re go­ing to do when we get a vac­cine, or if we don’t,” he says. “If the process of get­ting a vac­cine, test­ing it, prov­ing it, man­u­fac­tur­ing it, plan­ning for its de­liv­ery, and build­ing a vac­cine pro­gramme all over the world, if that’s go­ing to take as long as we think, then let’s fuck­ing start plan­ning it now.”

How will we live with the virus?

Peo­ple will have to adapt – and life will change. Hey­mann says we will have to get used to ex­ten­sive mon­i­tor­ing for in­fec­tions backed up by swift out­break con­tain­ment. Peo­ple must play their part too, by main­tain­ing hand wash­ing, so­cial dis­tanc­ing, and avoid­ing gath­er­ings, par­tic­u­larly in en­closed spa­ces.

Re­pur­posed drugs are faster to test than vac­cines, so we may have an an­tivi­ral or an an­ti­body treat­ment that works be­fore a vac­cine is avail­able, he adds. Im­me­di­ate treat­ment when symp­toms come on could at least re­duce the death rate.

Yuen Kwok-Yung, a pro­fes­sor of in­fec­tious dis­ease at the Univer­sity of Hong Kong, has ad­vised his govern­ment that all phys­i­cal dis­tanc­ing can be re­laxed – but only if peo­ple wear masks in en­closed spa­ces such as on trains and at work, and no food or drink are con­sumed at con­certs and cinemas. At restau­rants, ta­bles will have to be shielded, with wait­ers fol­low­ing strict rules to pre­vent spread­ing the virus. “In our Hong Kong per­spec­tive, the dili­gent and cor­rect use of re­us­able masks is the most im­por­tant mea­sure,” he says.

Sarita Robin­son, a psy­chol­o­gist who stud­ies re­sponses to threats at the Univer­sity of Cen­tral Lan­cashire, says peo­ple are still adapt­ing to the “new nor­mal” and that with­out more in­ter­ven­tions – such as fines for not wear­ing face masks – “we could see peo­ple drift­ing back to old be­hav­iours”.

We may be­come blase about Covid deaths when life re­sumes and the me­dia move on, but the se­ri­ous­ness of the ill­ness will make it harder to ig­nore, she says.

One last pos­si­bil­ity could save a lot of trou­ble. Some sci­en­tists won­der whether the com­mon cold coro­n­aviruses crossed into hu­mans in the dis­tant past and caused sim­i­lar ill­ness be­fore set­tling down.

“If the virus doesn’t change there’s no rea­son to think that mirac­u­lously in five years’ time it won’t still cause pneu­mo­nia,” says Perl­man. “But that’s the hope: that we end up with a much more mild dis­ease and you only get a bad cold from it.”

Hey­mann says it is too soon to know how the pan­demic will pan out. “We don’t un­der­stand the des­tiny of this virus,” he says. “Will it con­tinue to cir­cu­late after its first pan­demic? Or will it, like some other pan­demic viruses, dis­ap­pear or be­come less vir­u­lent? That we do not know.”

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